Submitted to: Proceedings of the National Academy of Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/14/2006
Publication Date: 5/23/2006
Citation: Chen, R., Neill, J.D., Estes, M.K., Prasad, B.V. 2006. X-ray structure of a native calicivirus: structural insights into antigenic diversity and host specificity. Proceedings of the National Academy of Sciences USA. 103(21):8048-8053. Interpretive Summary: Emerging or newly discovered viruses are becoming more of a threat to both human and animal health. Some of these viruses belong to the calicivirus family of viruses. Two groups of caliciviruses, Noroviruses and Sapoviruses, do not grow in cell cultures. Both groups are major causes of viral food poisoning. The inability to grow these viruses in the laboratory makes them difficult to study. To better understand the immune response against caliciviruses in general, San Miguel sea lion virus that grows well in the laboratory was studied. We constructed the first high resolution structure of a living calicivirus. From this we could determine which regions of the virus may be used in a protective immune response. This was compared to the structure of the non-living virus structure of a Norovirus to find which portion of this virus played the same role. Further research efforts can now be directed toward understanding of how vaccines can be generated that are effective in protecting against calicivirus infections. This information will allow researchers to understand immune responses against the caliciviruses and make useful veterinary and human vaccines possible.
Technical Abstract: Caliciviruses, grouped into four genera, are important human and veterinary pathogens with a potential for zoonosis. In these viruses, capsid related functions such as assembly, antigenicity, and receptor interactions are encoded in a single protein that forms an icosahedral capsid. Understanding of the immunologic functions and pathogenesis of human caliciviruses in the Norovirus and Sapovirus genera is hampered by the lack cell culture system or an animal model. Much of our understanding of these viruses including the structure has depended upon recombinant capsids. Here we report the first atomic structure of a native calicivirus from the Vesivirus genus that exhibits a broad host range possibly including humans, and for the first time map immunological function onto a calicivirus structure. The vesivirus structure, despite a similar architectural design as seen in the recombinant capsid of a norovirus, exhibits novel features and indicates how the unique modular organization of the capsid protein with interdomain flexibility, akin to an antibody structure with a hinge and an elbow, integrates the capsid related functions and facilitates strain diversity in caliciviruses. The internally located N-terminal arm participates in a novel network of interactions through domain swapping to assist the assembly of the shell domain into an icosahedral scaffold, from which the protruding domain emanates. Neutralization epitopes localize to three distinct hypervariable loops in the distal portion of the protruding domain surrounding a region that exhibits host-specific conservation suggesting a mechanism for antigenic diversity and host specificity in caliciviruses, and providing a structural framework for vaccine development.